The objective of this research program is to investigate the role of vitamin K-dependent processes involving proteins containing the amino acid, gammacarboxyglutamic acid (Gla), in calcific cardiovascular disease. Background work in this field has established the existence of a unique, extrahepatic class of vitamin K-dependent, calcium binding proteins. The most extensively studied of these is the bone protein, osteocalcin, which is the most abundant noncollagenous protein of bone. Osteocalcin has been demonstrated to bind calcium via Gla residues, which are synthesized as post-translational, enzymatic carboxylations of specific glutamic acid residues, analogous to the vitamin K-dependent blood coagulation factors. This work has lead to the present effort, in which Gla containing proteins have been demonstrated to occur in a number of calcific cardiovascular diseases including: calcified atherosclerosis; calcific aortic stenosis; xenograft valve calcific degeneration; and calcified deposits on artificial heart devices. Typically, no detectable Gla is found in hydrolysates of normal cardiovascular tissues. The planned research of the current program will explore in depth the role of Gla containing proteins as markers of pathogenesis will also be examined. The ultimate goal of this work is to achieve a better understanding of vitamin K depedent processes in cardiovascular disease, which may lead to improved therapeutic approaches via vitamin K antagonism or other means of regulating Gla containing protein synthesis and activity.